1-alkyl-2-phenyl-3-alkyl indanes and process of manufacture



Patented Jan. 3, 1950 1 2,493,729

1-ALKYL-2-PHENYL-3-ALKYL INDANES AND PROCESS OF MANUFACTURE Ulrich V. Solmssen, Essex Fells, N. J assignor to Hofimann-La Roche Inc., Nutley, N. J., a corporation of New Jersey No Drawing. Application October 23, 1946, Serial N0. 705,235

11 Claims. (Cl. 260-613) 2 The present invention relates to the production my invention, such indenes are converted into the of 1-alkyl-2-phenyl-3-a1kyl-indanes which can be indanes of Formula I by reacting the indenes with represented by the following general formula: aldehydes as, for example, formaldehyde, para- (D R formaldehyde, formaldehyde-yielding compounds 5 and the like to obtain the corresponding fulvenes.

R1 7 The fulvenes are then hydrogenated to yield the 1,3-dialkyl-Z-phenyl-indanes, the exocyclic and the 2,3-double bonds being simultaneously reduced. To obtain the hydroxy derivatives, the

RP 10 alkoxy or acyloxy derivatives are then dealkylated. The process can be represented by the folwherein R represents an alkyl radical which may lowing equation, wherein formaldehyde is embe a. straight-chain or a branched-alkyl, R1 repployed as the aldehyde.

CH1 11,0 on, on,

ECHO H,

catalyst 11, R;0-

dealkylation I R10 H0 a resents an oxygen containing radical, such as In the above equation R and R1 are alkyl hydroxyl, alkoxy and acyloxy and R2 represents radicals such as methyl, ethyl, propyl, and the alkyl. like. Inmy copending application, Serial No. 550,869, This process is particularly valuable for profiled August 23, 1944, now U. S. Patent 2,447,099, ducing new indanes of Formula I wherein the althere are disclosed indene derivatives of the fol kyl substituents in the 1- and 3-positions are lowing general formula: identical, as, for example, 1-methyl-2 -(p-hy- (m droxyphenyl)-3-methyl-6-hydroxy-indane; and Hi R1 wherein the alkyl substituents in said positions dififer from one another by more than 'one carbon atom, as for example, l-methyl-2- (p-methoxyphenyl)-3-isopropyl-6-hydroxy-indane. Another R1- 40 advantage of the process is that excellent yields are obtained thereby. wherein R1 has the same significance as in the By employingjndenesas tarting materials in above formula and R is a lower alkyl group which the 3-position is substituted by a branched taining at least two carbon atoms. In Salzer alkyl as, for m isopropyl isgbutyl Paten N there are disclosed tiary butyl, isoamyl and the like, the correspondpounds of Formula II, where R stands for a in 1 alkyl 3 branched alkyl indanes are methyl group only. The compounds of Formula t i d,

II are also disclosed in my article The synthesis The indanes comprising my invention have of estrogenic indene derivatives and remarks on pronounced estrogenlc activity and are suitable the configuration of stilbestrol, the Journal of 5 for administration orally, parenterally Sublimth Am ric n Ch mical Soci ty, v 65, p gually. The 1-alkyl-3-branched-alkyl-indanes 2370 (1930). are particularly characterized by their exception- The above-described indenes are empl y d as i ally high estrogenic activity in addition to their starting materials for the production of the comstability. j

p s f th p e nt i ven i According to When obtained in the form of the phenols, that of sulfuric acid. Propionates can be obtained by reacting the phenols with propionylchloride in.

pyridine. Other esters can be produced in similar manner.

The ethers can be prepared'by "the H phenols by alkylation with suitable alkylating agents-such as diazomethane, alkyl halides, such as methyl or ethyl chlorides or iodides; alkylsulfates, dialkyl H sulphates, or alkyl sulfites, as for instance, methyl or ethyl sulfates and sulfites in the presence of suitable acid-binding agents as, for example, potassium carbonate, silver oxide, sodium hydroxide and the like.

In general, the preferred method of practicing the process is to react a Z-(p-alkoxyphenyl) -3- alkyl-G-alkoxy-indene withan aldehyde as, for example, paraformaldehyde, to hydrogenate the resulting fulvene and then to wholly or partially dealkylate the dialkyl ether so obtained to convert at least one of thealkox'y groups into a hydroxyl. By controlling the dealkylation, only one alkoxy group can be dealkylated and the resultant free hydroxy group can then be acylated asdescribed above. In this way, mixedetheresters, can be obtained. Such mixed ether-esters of 1,3-dia1kyl-2-hydroxyphenyl-hydroxy-indanes have the advantage of having a more prolonged estrogenic activity as compared with the dihydroxy compounds.

In the manner described, compounds corre-- sponding to the Formula I can be prepared where R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl and the like, as for example:

1-methy1-2-(p-hydroxyphenyl) -3-methyl-6 hydroxy-indane l-methy1-2- (p-methoxyphenyl) -3- methyl-6 hy- The maximum estrogenic activity is exhibited by those compounds containing a branched alkyl radical in the 3-position, particularly those containing an isopropyl radical in this position. Such isopropyl compounds have been found to be active in doses of about one microgram when givensubcutaneously and 5.6.v micrograms when given orally in. ovarectomized rats.

The 3-branched-alkyl-indenes whichare employed as starting materials to produce theala1kyl-3 -branched-alk yl-indanes may be prepared 4' according to the general procedure described in my above-mentioned article. Thus, by reacting in the same manner as described the indanone (XVI) with a branched alkyl magnesium halide as, for example, any one of the following: isopropyl magnesium iodide, isobutyl magnesium iodide, tertiary butyl magnesium iodide; the corresponding 2 (p-methoxyphenyl)-3-(isopro- 'pyl; -isobutyl and -tertiary butyl) -6-methoxy-indenes are obtained. a

The following examples will serve to illustrate the invention:

, XAMPLE A Preparation of 2 (p methoxyphenyl) 3-isopropyZ-G-methoaty-indene 4.54 grams of magnesium metal turnings and 18 cc. of absolute ether are placed in an apparatus for preparing Grignard reagent and 31.7 grams of isopropyl iodide added in such a manner that methoxy-l-indanone dissolved in benzol is added dropwise. After the addition the mixture is refluxed for a further two hours and after cooling, 25 cc. of 5 per cent sulfuric acid are slowly added, the mixture warmed for half an hour and the reaction mixture then allowed to separate into two M layers. The ether layer is removed, washed'with water and dried over sodium sulfate. After filtration the other solution on evaporation leaves a crystalline residue which, on crystallization from methanol yields 2 (p methoxyphenyl) -3-isopropyl-6-methoxy-indene melting at 134.5-1'355" C. y

EXAMPLE B Preparation of 2- (p-methozcyphen'yl) -3-2'sobutyl- G-methoxy-indene The Grignard reagent is prepared from 9.07 grams of magnesium, cc. of absolute ether and 68.6 grams isobutyl iodide in the manner given inExample A. To this, 20 grams of Z-(pmethoxyphenyl) 6 methoxy 3 indanone dissolved in 380 cc. of benzol are added dropwise and after the addition the mixture. is refluxed for two hours and then decomposed with ice with 25 cc. of '5 per cent sulfuric acid. The mixture is warmed for half an hour, the ether layer removed, washed, dried with sodium sulfate and filtered. The ether solution on evaporation gives a crystalline residue which, on recrystallization twice from methanol, yields Z-(p-methoxyphenyl) -3-isobutyl 6 methoxy-indene melting at 75.5-76.5 C.

When tertiary butyl iodide is employed in forming the Grignard agent instead of isobutyl iodide in the same manner is described in Example B, and this reacted with the sameindanone, as described, there is obtained Z-(p-methoxyphenyh- '3-tertiary butyl-G-methoxy-indene.

EXAMPLE 1 Preparation of I-methylene-Z-(xi-methoxyphenyl) -3-aZkyl-6-methoa:y-indenes A fulvene is prepared by refluxing on the steam bath under nitrogen, a solution of 0.02 mol of the 2--(p-methoxyphenyl) -3-methyl-6-methoxyindene in the necessary amount of absolute ethanol for solution with 1.53 grams of paraformaldehyde and 7.5 cc. of 28 per cent potassium hydroxide in absolute methanol. After refluxing, the mixture is diluted with water and, the fulvene is extracted with ether from the alkaline solution. Theether. extract is Washed until neutral, dried and'va'porated under vacuum. The residue is an. oil which crystallizes in a crude stage and is recrystallized from 80 per cent ethanol. In this manner v there is obtained 1-methylene-2- (p.- methoxyphenyl) -3-methyl 6 methoxy-indenethe corresponding l-methylene-derivatives of compounds a, b, c and d are obtained which have the following melting points, respectively:

a. 96.5-97 C. b. 68--'71.5 C. c. 129-133 C. d. B. P. 190-200/0.1 mm.

EXANLPLE 2 Preparation of l-methyl-z-(p-methoxyphenyl) 3-aZIcyl-6-indanes The fulvenes described in Example 1 are hydrogenated in ethanol with Raney nickel at 40 pounds pressure. The hydrogenation products are generally obtained as colorless oils. On fractionation of the hydrogenation product in vacuo, the following compounds are obtained:

1-methyl-2 (p methoxyphenyl) 3 methyl-6- methoxy-indane, B. P. 1'70/0.'7 mm.

l-methyl 2 (p methoxyphenyl) 3 ethyl-6- methoxy-indane, B. P. 170/0.6 mm.

l-methyl- 2 -(p methoxyphenyl) 3 propyl-6- methoxy-indane, B. P. 150-160/0.1 mm.

1-methyl-2- (p-methoxyphenyl) 3 isopropyl-fimethoxy-indane l-methyl 2 (p methoxyphenyl) 3 butyl-6- methoxy-indane, B. P. 175180/0.2 mm.

EXAMPLE 3 Preparation of I-methyZ-Z- (p-hydroxyphenyl)- 3-alkyl-6-hydrory-indanes The dialkoxy compounds obtained as described in Example 2 are dealkylated by refluxing one part of each compound with 10 volumes of a mixture of three parts of acetic acid and one part of 40 per cent hydrobromic acid until a sample is soluble in alkali. In the event that prolonged refluxing does not result in a completely alkalisoluble product, a small amount of alkali-soluble material is removed by ether extraction. The alkaline solution is then acidified to Congo paper and extracted with ether. The residue after evaporating the ether is repeatedly recrystallized from 50 per cent methyl alcohol. In this manner the following compounds can be obtained:

l-methyl 2 (p-hydroxyphenyl) 3 methyl-6- hydroxy-indane, M. P. 195-196 C.

l=methyl M 2 (p-hydroxyphenyl) 3 ethyl 6- hydroxy-indane, M. P. 195-198 C.

1 methyl 2 (p-hydroxyphenyl) 3 propyl-6- hydroxy-indane, M. P. 184-485 C.

l-methyl 2 (p-hydroxyphenyl) -3-isopropyl-6- hydroxy-indane, M. P. 174.5 181" C, v l-methyl 2 --(phydroxyphenyl) 3- butyl 6- hydroxy-indane, M. P. 175-182" C.

The dihydroxy compounds as prepared accord-..

ing to Example 3 can be, if desired, subsequently acyla'ted'or alkylated to form the corresponding I esters or others, such as the diesters and diethers or the monoesters and 'monoethers. By partial dealkylation of the compounds formed by the process illustrated in Example 2, followed by esterification, there can also be obtained the ether esters.

While the above examples illustrate the process as carried .out with formaldehyde, thereby producing'the 1 methyl-2-phenyl-3-alkyl-indanes, it. is to be understood that the process may be carried out with other aldehydes as, for example, acetic aldehyde, propyl aldehyde, butyric aldehyde, and the like. When employing acetaldehyde in a manner similar to that described above, the l-substituent is an ethyl group. Similarly, when employing propyl aldehyde and butyric a1- dehyde, the l-substituent in the indane becomes propyl and butyl, respectively.

Since the fulvenes which are obtained as intermediates are new compounds, it is to be understood that they also form part of the present invention.

I claim:

1. The process which comprises reacting with an aldehyde a compound of the following formula:

H,C{ R1 in which R. is selected from the group consisting of alkyl and branched alkyl, R1 is an alkoxy radical, and hydrogenating the resulting compound.

2. A process of preparing a l-alkyl-Z-(p-hydroxyphenyl) 3 alkyl-G-hydroxy-indane which comprises reacting a 2-(p-a1koxyphenyD-3-alkyI-G-aIkoXy-indene with an aldehyde, hydrogenating the fulvene obtained and converting the alkoxy groups of the resulting indane to hydroxyls by dealkylation.

3. A process as in claim 2 in which the aldehyde is formaldehyde.

4. A process of preparing fulvenes which comprises reacting z-(p-alkoxyphenyl) -3-a1kyl-6- alkoxy-indenes with an aldehyde.

5. A process as in claim 4 wherein the aldehydeis formaldehyde.

6. A process of preparing 1-a1kyl-2-(p-alkoxyphenyl)-3-alkyl-6-alkoxy-indanes which comprises hydrogenating fulvenes of 2-(p-alkoxyphenyl) -3-alky1-6-alkoxy-indenes.

mixed v Certificate of Correction Patent No. 2,493,729

January 3, 1950 ULRICH V. SOLMSSEN It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows:

Column 1, line 52, for (1930) read (1948); column 3, line 13, for by read from; column 4, line 61, for is read as; column 6, line 73, for metho read methoxy-indene;

Xy indene t e same may conform to the record Signed and sealed thi THOMAS F. MURPHY,

Assistant Oommz'asz'oner of Patenta. 

2. A PROCESS OF PREPARING A 1-ALKYL-2-(P-HYDROXYPHENYL)-3-ALKYL -6- HYDROXY-INDANE WHICH COMPRISES REACTING A 2-(P-ALKOXYPHENYL)-3-ALKYL-6-ALKOXY-INDENE WITH AN ALDEHYDE, HYDROGENATING THE FULVENE OBTAINED AND CONVERTING THE ALKOXY GROUPS OF THE RESULTING INDANE TO HYDROXYIS BY DEALKYLATION. 